Plasma levels of high-density lipoprotein (HDL) cholesterol and the major HDL apolipoprotein apo-A-1 are inversely associated with atherosclerotic cardiovascular disease. Factors, which regulate their levels, are poorly understood at the molecular level. Plasma HDL cholesterol and apoA-1 levels are determined in part by the rate at which they are catabolized, but the mechanisms that modulate their catabolism in vivo remain incompletely understood. Both acute and chronic inflammatory states are associated with low levels of HDL cholesterol and apoA-1, primarily due to increased catabolism. The group 11 secretory phospholipase A2 (sPLA2) is synthesized constitutively by vascular smooth muscle vascular inflammatory condition and is associated with increased amount of sPLA2 within the vessel wall. The investigators have demonstrated that systemic overexpression of sPLA2 in mice results in accelerated catabolism of HDL with increased uptake of HDL cholesteryl ester in the liver and adrenals and of apoA-1 in the kidneys. Furthermore, the investigators recently reported the isolation and characterization of a new member of the lipoprotein lipase gene family termed endothelial lipase (EL) that is made by endothelial cells and has primarily phospholipase activity. The investigators have demonstrated that systemic overexpression of EL in mice also causes markedly increased catabolism of HLD cholesteryl ester and apoA-1. The major underlying hypothesis of this proposal is that extracellular phospholipases, such as sPLA2 and EL, are synthesized constitutively within the vessel wall and upregulated in response to local inflammatory mediators (such as those associated with atherosclerosis) and that they modulate system HDL metabolism through hydrolysis of HDL phospholipids at the site of the vessel wall.